2-ME and Arsenic Trioxide Boost Cell 02- and Kill CLL Cells

[Guest guest]

(We posted an abstract from the AACR meeting last year; this paper is

similar in conclusions.)

Blood First Edition Paper

prepublished online January 16, 2003

Free radical stress in chronic lymphocytic leukemia cells and its

role in cellular sensitivity to ROS-generating anticancer agents

Yan Zhou, O Hileman, Plunkett, J Keating,

and Peng Huang*

Department of Molecular Pathology, The University of Texas M. D.

Cancer Center, Houston, TX, USA

Department of Experimental Therapeutics, The University of Texas M.

D. Cancer Center, Houston, TX, USA

Department of Leukemia, The University of Texas M. D. Cancer

Center, Houston, TX, USA

* Corresponding author; email: phuang@...

<mailto:phuang@...>.

2-Methoxyestradiol (2-ME), a new anticancer agent currently in

clinical trials, has been demonstrated to inhibit superoxide

dismutase (SOD) and induce apoptosis in leukemia cells through a free-

radical-mediated mechanism. Because the accumulation of superoxide

(O2-) by inhibition of SOD depends upon the cellular generation of O2-

, we hypothesized that the endogenous production of superoxide may be

a critical factor that affects the anti-leukemia activity of 2-ME.

In the present study, we investigated the relationship between

cellular O2- contents and the cytotoxic activity of 2-ME in primary

leukemia cells from 50 patients with chronic lymphocytic leukemia

(CLL). Quantitation of O2- revealed that the basal cellular O2-

contents are heterogeneous among CLL patients. The O2- levels were

significantly higher in CLL cells from patients with prior

chemotherapy. CLL cells with higher basal O2- contents were more

sensitive to 2-ME in vitro than those with lower O2- contents. There

was a significant correlation between the 2-ME-induced O2- increase

and the loss of cell viability. Importantly, addition of arsenic

trioxide, a compound capable of causing reactive oxygen species (ROS)

generation, significantly enhanced the activity of 2-ME, even in the

CLL cells that were resistant to 2-ME alone. T

hese results suggest that the cellular generation of O2- plays an

important role in the cytotoxic action of 2-ME, and that it is

possible to use exogenous ROS-producing agents such as arsenic

trioxide in combination with 2-ME to enhance the anti-leukemia

activity and to overcome drug resistance. Such a combination strategy

may have potential clinical applications.